This proposal seeks funding to purchase a ThermoFisher Q-Exactive rapid scanning high-resolution mass spectrometer with appropriate software that will become part of the drug metabolism and pharmacokinetic (DMPK) core dedicated to the study of small molecule disposition in vitro and in animals. This shared instrument will expand capabilities and support a range of research projects originating from sixteen NIH funded projects from seven institutions. The level of engagement for each of these projects with the DMPK core is high as demonstrated by the financial commitments in the respective grants to cover portions of technician salary and experimental expenses (13 of 16 investigators) or through chargebacks that are specifically written into grants (3 of 16). We present justification for the purchase of a Q-Exactive mass spectrometer system by demonstrating significant increases to the information content obtained from metabolism experiments performed using high resolution mass spectrometry. Incorporation of this new technology allows for the simultaneous acquisition of high-performance qualitative and quantitative data from complex samples. The current mass spectrometers in the Scripps DMPK core are triple-quadropole instruments ideally suited for determination of drug concentrations in plasma or other tissues, but lacking high resolution and mass accuracy which are essential for the characterization of unknown metabolites. Samples were prepared as Scripps Florida and sent to application specialists at three vendors for evaluation of the ThermoFisher Q-Exactive, the ABSciex 5600 tripleTOF, and the Waters Synapt G2 QTOF. The presented data demonstrates the benefits each major users will derive from the incorporation of high resolution mass spectrometry that are not currently possible with existing equipment. Data is also presented to rationalize the choice of the Q-Exactive over the other excellent systems. The majority of the grants that benefit from the shared instrument are probe optimization, translational science, and drug discovery grants. Significant increases in capacity to elucidate metabolic liabilities of individual compounds during the optimization phase will increase project productivity. Compound optimization is an iterative process and understanding the drug metabolism and pharmacokinetic properties of molecules at an early stage allows the whole molecule to be optimized instead of just the biochemical or cellular potency. This shared instrument will be installed in the Scripps Florida Mass Spectrometry Laboratory and will be maintained by a group of experienced mass spectroscopists, the PI and two senior research technicians. Several Post Doctoral fellows will be trained or continue their training on this instrument.